MYOCARDIAL HYPERTROPHY AND HEART FAILURE

Project Details

Description

This program project represents a multi-disciplinary approach to the
problem of myocardial hypertrophy and heart failure. Physiologic studies
will be conducted in conscious chronically instrumented animals, to avoid
the complicating effects of anesthesia and recent surgery on the LV
contractile state and on neural control of the heart and coronary
circulation. Tissues from these physiological models will be utilized for
biochemical, molecular biological and pathological studies. Project #1
represents a continuation of studies on alterations in LV function and
myocardial perfusion induced by LV hypertrophy and failure that have
evolved in the laboratory of Dr. S. Vatner. Of particular importance are
the recent studies conducted in collaboration with Drs. C. J. Homcy and D.
E. Vatner of Mass. General Hospital, finding alterations in Beta-adrenergic
and muscarinic receptor control of the hypertrophied and failing heart.
Accordingly, a major goal of this component of the application will be to
determine whether the previously observed reduction of high affinity
Beta-adrenergic agonist binding sites, adenylate cyclase stimulation, and
muscarinic receptors induce corresponding physiological deficits in models
of LV hypertrophy and failure. Another major goal is to determine whether
limitations in subendocardial perfusion or diastolic compliance are
responsible for alterations in subendocardial systolic function in LV
hypertrophy and failure. Concomitantly, Drs. c. Homcy, D. Vatner, B.
Nadal-Ginard, G. Matsueda, and R. Graham will further examine the cellular
and molecular mechanisms related to alterations in adrenergic and
muscarinic receptor regulation in LV hypertrophy and failure (Project 2).
The studies on limitations of myocardial perfusion will be carried out from
an anatomic and pathologic viewpoint by Drs. Bishop and Anderson in Project
3. The studies on LV function will also be carried out in collaboration
with Dr. I. Mirsky, who is proposing to test a novel hypothesis involving
concepts of myocardial mechanics, i.e., end systolic myocardial stiffness
is independent of end-systolic stress (Project 5). The changes in
myocardial stiffness and compliance observed with LV hypertrophy and
failure should be an important factor in the regulation of atrial
natriuretic factor. This problem, i.e., to determine how stimulus-release
and effector mechanisms of atrial natriuretic factor are altered in the
presence of LV hypertrophy and failure, will be addressed by Drs. Graham,
Homcy, and Young in Project 4.
StatusFinished
Effective start/end date12/31/896/30/97

Funding

  • National Heart, Lung, and Blood Institute
  • National Heart, Lung, and Blood Institute
  • National Heart, Lung, and Blood Institute
  • National Heart, Lung, and Blood Institute
  • National Heart, Lung, and Blood Institute
  • National Heart, Lung, and Blood Institute
  • National Heart, Lung, and Blood Institute

ASJC

  • Medicine(all)
  • Cardiology and Cardiovascular Medicine
  • Biochemistry
  • Biomedical Engineering

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